We have continued our studies of the opioid receptor-endorphin system from medicinal chemical and pharmacological directions. This system consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types and their subtypes located in anatomically well defined areas of the mammalian CNS with the numerous endogenous opioid peptides (endorphins) which subserve these receptors. These results present many opportunities for research highly relevant to drug abuse and for the development of new medications that act on these receptors. The opioid receptor endorphin system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state including regulation of dopamine (DA) levels in the nucleus accumbens (NAC) and expression of the effects of alcohol and cocaine. This system is dysregulated by the abuse of heroin and prescription narcotics resulting in tolerance and dependence. Recent pharmacologic advances have shown that moderately selective delta opioid antagonists suppress (a) cocaine seeking behavior, (b) heroin self-administration and (c) the development of tolerance and dependence to the mu agonist morphine. The former two observations strongly indicate that highly selective delta receptor antagonists might be valuable medications for the treatment and prevention of human cocaine and narcotic abuse and perhaps other undesirable reinforcing behaviors. The latter observation suggests that a drug showing a mu agonist-delta antagonist profile might produce strong analgesia without producing tolerance and dependence thus allowing continuous treatment of chronic pain. The exploitation of these and other similarly intriguing observations now requires novel, exquisitely selective, nonpeptide ligands as research tools and potential medications. These new tools will enable the study of many questions of fundamental importance concerning the function of mu, delta and kappa opioid receptor subtypes and how drugs interact with their receptors to elicit these functions. We have continued to design, synthesize and evaluate novel drugs for this purpose during the reporting period. The 5-phenylmorphans are a particularly interesting class of opioid receptor agonists that were originated by Everette May at NIH in 1955. We earlier identified a mu agonist-delta antagonist and a delta inverse agonist in this series. We have now identified a morphine-like mu agonist and also a mu antagonist in a series of conformationally restrained 5-phenylmorphans. The diverse profiles obtained in this series illustrate the importance of subtle changes on the carbon-nitrogen skeleton and careful attention to stereochemical detail and provide important leads toward novel pain medications with reduced side effects and further understanding of drug-receptor interactions. We are now addressing the major unanswered question of the optimum degree of mu agonism and either delta agonism or antagonism in a single compound for the ideal strong analgesic. We are presently pursuing this question in primate studies in collaboration with Steve Negus at the Medical College of Virginia who is utilizing our delta agonist SNC80 and other related compounds in combination with strong mu agonists. We have also identified systemically active drugs in the unbridged phenylmorphan series that show mu agonism and delta antagonist activity in the same compound. We are presently extending this work in (a) oxide-bridged and (b) nonbridged 5-phenylmorphans, and (c) other appropriate partial structures. Collaborative computer assisted molecular modeling and ab initio quantum mechanical methods are being employed in the design of these compounds. These novel drugs are being studied in the appropriate in vitro binding assays in native and cloned systems, smooth muscle assays, in vivo assays in small animals, and self-administration and other studies in rhesus monkeys. We recently found that 20R-epoxyresibufogenin formate (20R-ERBF) is systemically available and orally effective in blocking chronic pain in animal models of bone cancer pain and pancreatitis by antagonizing interleukin 6 (IL-6). We characterized it as a reversible IL-6 receptor antagonist with femtomolar affinity that acts through peripheral mechanisms. The only presently available human therapy for IL-6-related disorders is tocilizumab, an expensive (15-20K/year/patient), monoclonal antibody against the IL-6 receptor itself. Nevertheless, the clinical effectiveness of tocilizumab validates the mechanism of suppressing IL-6 function and the notion that a small molecule antagonist of the IL-6 should be a much more advantageous treatment for inflammatory pain than an antibody against the IL-6 receptor. In addition, it is well known that excessive levels of IL-6 play a role in the pathogenesis of a number of disorders including rheumatoid arthritis, Crohn's disease, multiple sclerosis, Castleman's disease, and certain types of leukemias and tumors, as well as depression, cardiomyopathy, and atherosclerotic disease, osteoporosis, diabetic neuropathy. A clinically acceptable, small molecule IL-6 antagonist should also be useful in treating these disorders and offer great advantages over tocilizumab therapy. Such treatment could offer distinct advantages to the use of narcotics that produce dependence, tolerance and in some cases life-threatening constipation. Combination of the IL-6 antagonist with narcotic therapy for severe pain should lower the dose of narcotic required and thus reduce narcotic-mediated side effects. In summary, we have identified 20R-ERBF (7) as an orally effective IL-6 receptor antagonist that blocks chronic pain in two animals models and provides an important lead to novel nonnarcotic agents for the treatment of pain. This compound or a derivative may also offer great advantages over an expensive biological treatment to block the actions of IL-6 and provide a novel therapeutic for a number of disease states.